Resveratrol Attenuates Obesity by Inducing GDF15 Expression via the p38-ATF3 Signaling Pathway

Resveratrol, a natural polyphenol, has been widely studied for its potential health benefits in obesity treatment, but its molecular mechanism remains elusive. This study investigates the molecular mechanisms by which resveratrol promotes the expression and secretion of Growth Differentiation Factor 15 (GDF15), a key regulator of energy homeostasis. Using both murine embryonic fibroblasts (MEFs) and human HepG2 cells, resveratrol dose-dependently upregulates Gdf15 mRNA and protein expression, as well as increases GDF15 secretion. Transcriptome analysis and subsequent validation experiments revealed that Activating Transcription Factor 3 (ATF3) mediates the effect of resveratrol on GDF15 expression. Additionally, resveratrol-treated mice exhibited resistance to high-fat diet-induced obesity and increased plasma GDF15 levels. In vivo studies in mice further confirmed that resveratrol treatment elevates GDF15 levels in liver, kidney, and colon tissues, and enhances downstream ERK signaling in the brain. Collectively, these findings suggest that GDF15 plays a critical role in mediating the anti-obesity effects of resveratrol.